Alterations in cognitive function may lead to altered state of consciousness, or to altered cognitive function, and may manifest in memory impairment, or learning disabilities, or any type of altered function.
Attention deficit hyperactivity disorder (ADHD) is characterized by pervasive and impairing symptoms of inattention, hyperactivity, and impulsivity. ADHD/ADD is one of the most thoroughly researched disorders in medicine. It has been associated with a broad range of negative outcomes for affected subjects and with serious financial burden to families and society, which marks it as a major public health problem.
Amnesia is a condition which can be defined by loss of memory due to some disturbing or appalling psychological experience, brain injury or chain of emotional events. There are different reasons and causes of amnesia such as organic or functional reasons. Organic amnesia is caused due to damage to the brain by external factors which can be due to physical impacts like trauma or disease. Functional amnesia is due to psychological factors. There are many reasons which can be the cause of amnesia-like phenomena: head injury, severe illness, high fever, seizures, emotional shock or hysteria, alcohol-related brain damage, drugs, stroke, Alzheimer's disease and brain surgery, any type of metabolic disease such as hepatic or uremic encephalopathy, any disease that altered blood flow in the brain, or altered neurotransmission in the brain, or is the result of increase or decrease in any type of metabolite in the brains, any disease associated with accumulation of amyloid in the brain, or with the alteration of electrical function, or metabolic function, or any type of altered mechanism in the brain.
Fatigue is related to most lifestyle habits and mental health conditions. The literature describes fatigue as a complex phenomenon that represents decreased ability to perform or accomplish mental or physical tasks or respond after extended activity as well as decreased motivation to perform tasks. The level of fatigue experienced by an individual relates to past cumulative daily activity patterns and to periods of sleep and activity. In summary, fatigue results from time spent on tasks, natural circadian factors, and inadequate sleep. Alertness, on the other hand, is the state of readiness and attentiveness achieved without artificial or natural enhancements.
Having difficulties with concentrating is a symptom that can arise from both physical and psychological or emotional problems. Symptoms of lack of or deficiency in concentration may or may not be associated with other memory-related symptoms such as forgetfulness. Physical medical conditions that affect concentration include Lyme disease, whiplash, and various others. Psychological conditions that may impair concentration include depression, certain anxiety disorders, and stress. Sleep disorders such as insomnia or sleep apnea can also impair concentration ability.
Metadoxine is a pyridoxine-pyrrolidone carboxylate (also known as pyridoxol L,2-pyrrolidon-5 carboxylate or pyridoxine 5-oxo-2-pyrrolidon-carboxylate) with significant alcohol scavenging properties. Metadoxine has been used to treat acute alcohol intoxication, poisoning, and certain other acute alcohol syndromes (reviewed in Addolorato et al., Int. J. Immunopathol. Pharmacol. (2003) 16:207-214). Long term data show that metadoxine is safe for use by humans.
Metadoxine accelerates the elimination of alcohol from the blood and tissues, helping restore the functional structure of the liver and alleviate neuro-psychological disorders associated with chronic alcohol intoxication and related syndromes. In animal studies, metadoxine increased plasma clearance and urinary excretion of ethanol, inhibited the increased production of fatty acid esters in the liver during chronic alcohol intake, reduced oxidative stress and prevented glutathione depletion in hepatic tissues (Antonelli et al., Pharmacol. Res. Commun. (1984) 16:189-197). In the brain, metadoxine increased the level of GABA and acetylcholine in the frontoparietal cortex of guinea pigs.
Metadoxine is an ion-pair between pyrrolidone carboxylate (PCA) and pyridoxine (vitamin B6) with the two compounds linked in a single product by salification. The pairing with PCA synergistically increases the pharmacological activity of pyridoxine (see, e.g., U.S. Pat. No. 4,313,952). Metadoxine is freely soluble in water and in gastric fluid. Oral absorption of the drug is fast with high bioavailability (60-80%). The half life of metadoxine in human serum is short (40-60 minutes) without appreciable differences between oral and intravenous administration (Addolorato et al., supra; Lu Yuan et al., Chin. Med. J. 2007 120(2) 160-168).
Metadoxine is marketed in several countries as a prescription drug in the form of 500 mg tablets and 300 mg injections. Tablets contain 500 mg of metadoxine, microcrystalline cellulose and magnesium stearate. Ampoules contain 300 mg of metadoxine, sodium metabisulfite, EDTA sodium, methyl-p-hydroxybenzoate and water.
U.S. Pat. No. 6,541,043 describes a composition and method for treating Attention Deficit/Hyperactivity Disorder (ADHD), the composition comprising dimethylaminoethanol (DMAE), together with a variety of agents, inter alia vitamin B6, optionally with conventional drugs for treating ADHD. WO03/003981 discloses compositions for the structural/functional nutritional support for subjects with poor focus, concentration and/or memory, as well as subjects who subjectively experience transient mental fatigue or poor cognitive function. These compositions comprise, inter alia B-complex vitamins, including B6, and L-pyroglutamic acid, together with a large number of other ingredients. WO09/004,629 describes a method for decreasing or preventing symptoms or effects of alcohol consumption comprising administration metadoxine. US20070248696 describes a composition for improving neuromuscular facilitation, also known as “muscle memory,” and enhancing cognitive functions, such as memory and mental focus, in the form of a dietary supplement that comprises, amongst many ingredients, also vitamin B6. US20090081179 discloses the use of polyunsaturated fatty acids and e.g. vitamin B6 amongst others, in treatment of patients suffering from Parkinson's disease, Huntington's chorea, epilepsy, schizophrenia, paranoia, depression, sleep disorders, impaired memory function, psychoses, dementia and ADHD. EP 511943 describes pyroglutamic acid derivatives as enhancers of learning processes and memory. The effect of administration of metadoxine on memory recovery was tested on abstinent chronic alcoholic. Vitamin B6 was administered to a control group of similar patients. It was found that metadoxine helps recovery of short-term memory after 1-2 months of abstinence, and that its effect was superior to that of vitamin B6 [ Sinforiani et al., Clin. Trials J., 27(2):103-111 (1990)]. WO2010/013242 discloses salt adducts comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted, methods of their preparation, and pharmaceutical compositions and medicaments comprising them for the treatment of diseases or disorders associated with or inflicted by alcohol consumption.
There exists a need for methods able to treat, alleviate the symptoms of, relieve, improve and prevent a cognitive disease, disorder or condition, cognitive behavior and functioning, and maintain these improvements for prolonged duration.
It is an object of the invention to provide methods for treating such cognitive disorders and deficiencies using metadoxine and derivatives thereof or compositions comprising thereof. It is another object of the invention to provide compositions comprising metadoxine or derivatives thereof, for long-term treatment of cognitive deficiencies. These and other objects of the invention will become apparent as the description proceeds.